Ganglioside complexes as targets for antibodies in Miller Fisher syndrome.
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Autoantibodies↗
Biomedical subjects
H J Willison
Publications and source records attributed to H J Willison.
Basic and clinical aspects of autoimmune disorders in peripheral nerves.
This presentation discusses the immunobiology of the Guillain Barré syndromes (GBS), the world's leading cause of acute autoimmune neuromuscular paralysis. By gaining an understanding of the clinical and pathophysiological pathways operating in GBS, we can hope to develop novel immunotherapies that will improve clinical outcome. Here we focus on GBS mediated by anti-ganglioside antibodies and highlight the correlations between anti-ganglioside antibody patterns and clinical phenotypes, the development of models of GBS, and the application of novel therapies based on inhibition of complement activation.
Antibodies↗
A randomized controlled trial of recombinant interferon-beta 1a in Guillain-Barré syndrome.
The authors recruited 19 nonambulant patients with Guillain-Barré syndrome into a pilot, double-blind, randomized, placebo-controlled safety trial of interferon beta 1a (IFN[beta]-1a) (Rebif). Participants received IFN[beta]-1a or placebo subcutaneously three times weekly, 22 microg for the first week and then 44 microg for up to 24 weeks, in addition to IV immunoglobulin (IVIg). IFN[beta] did not have any unexpected interaction with IVIg and there was no significant difference in rate of improvement.
Cytokines↗
Apolipoprotein E genotypes and clinical outcome in Guillain-Barré syndrome.
BACKGROUND: Polymorphism of the gene encoding the cholesterol transport protein apolipoprotein E (APOE, gene; apoE, protein), known to be involved in axonal regeneration and remyelination, influences outcome after a variety of central nervous system disorders. Apolipoprotein E gene polymorphisms could affect recovery from Guillain-Barré syndrome. OBJECTIVE: To correlate APOE genotypes with residual disability and degree of improvement in Guillain-Barré syndrome, assessed one year after presentation METHODS: 91 patients with the syndrome were recruited from southeast England and their APOE genotypes were determined. RESULTS: There were no clear differences in APOE genotype or allele frequencies when comparing the 91 patients with controls, nor when comparing 81 patients with good outcome and 10 with poor outcome. CONCLUSIONS: APOE genotype did not influence susceptibility to Guillain-Barré syndrome or recovery from it. This may be because our sample size of 91 was not sufficiently large to detect small differences in recovery associated with different APOE genotypes, or because cholesterol transportation is not a crucial rate limiting step in peripheral nerve regeneration.
Adolescent↗
Roles of complex gangliosides at the neuromuscular junction.
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Animals↗
Structure of Campylobacter jejuni lipopolysaccharides determines antiganglioside specificity and clinical features of Guillain-Barré and Miller Fisher patients.
Ganglioside mimicry in the lipopolysaccharide (LPS) fraction of Campylobacter jejuni isolated from Guillain-Barré syndrome (GBS) and Miller Fisher syndrome (MFS) patients was compared with isolates from patients with an uncomplicated enteritis. The antibody response to C. jejuni LPS and gangliosides in neuropathy patients and controls was compared as well. LPS from GBS and MFS-associated isolates more frequently contained ganglioside-like epitopes compared to control isolates. Almost all neuropathy patients showed a strong antibody response against LPS and multiple gangliosides in contrast to enteritis patients. Isolates from GBS patients more frequently had a GM1-like epitope than isolates from MFS patients. GQ1b-like epitopes were present in all MFS-associated isolates and was associated with anti-GQ1b antibody reactivity and the presence of oculomotor symptoms. These results demonstrate that the expression of ganglioside mimics is a risk factor for the development of post-Campylobacter neuropathy. This study provides additional evidence for the hypothesis that the LPS fraction determines the antiganglioside specificity and clinical features in post-Campylobacter neuropathy patients.
Antibodies, Bacterial↗
Anti-glycolipid antibodies in the diagnosis of autoimmune neuropathies.
Recent years have seen major progress in our understanding of the clinical pathophysiology of autoimmune neuropathies particularly with the identification and analysis of antibodies to gangliosides and related glycolipids in the serum of patients. Anti-glycolipid antibodies react with epitopes on the carbohydrate region of glycolipid molecules and can be routinely measured by standard immunoassays. In multifocal motor neuropathy, IgM anti-GM1 antibodies that cross react with GD1b and asialo-GM1 are detectable in around 50p. 100 of cases. This condition may clinically resemble certain forms of lower motor neurone disease. IgM anti-GD1b antibodies are found in IgM paraproteinaemic neuropathy characterised by profound sensory ataxia. In the anti-myelin associated glycoprotein (anti-MAG) IgM paraproteinaemic neuropathy, antibodies also react with the acidic glycolipids, sulphated glucuronyl paragloboside and its higher lactosaminyl homologue (SGPG and SGPLG). Thus a variety of chronic syndromes can be defined by their anti-glycolipid antibody profile. In Guillain-Barré syndrome, anti GM1, GM1b, GD1a and GalNAc-GD1a antibodies are found in patients with acute motor axonal neuropathy (AMAN) and anti-GQ1b IgG antibodies are a very sensitive and specific marker for the Miller Fisher syndrome. Many other anti-glycolipid antibodies are being increasingly identified in other neuropathy subtypes. The article will summarise existing clinical and serological information in this field.
Acute Disease↗
Antiganglioside antibodies in acute self-limiting ataxic neuropathy: incidence and significance.
Antidisialosyl antibodies have been previously associated to chronic and acute ataxic neuropathies. We studied the presence of these antibodies in nine patients with acute self-limiting ataxic neuropathy (ASLAN) using ELISA and TLC immunodetection. One patient showed serum IgG immunoreactivity against gangliosides GD3 and GQ1b. The patient's IgG was able to bind to the nodes of Ranvier on frozen human dorsal root. Our studies confirmed that antidisialosyl reactivity is associated to ataxic neuropathy and its specific binding to the dorsal root could explain the predominant sensory involvement. Nevertheless, the low incidence of this reactivity indicates that a different pathogenic mechanism should be involved in most ASLAN patients.
Acute Disease↗
Guillain-Barré syndrome serum and anti-Campylobacter antibody do not exacerbate experimental autoimmune neuritis.
To investigate whether antibodies are pathogenic in Guillain-Barré syndrome (GBS), we injected pre-treatment serum from 11 GBS patients intraperitoneally into rats in which the blood-nerve barrier had been opened by induction of mild adoptive transfer experimental autoimmune neuritis. There was no significant clinical, neurophysiological or pathological difference between rats receiving GBS serum compared with those receiving control serum, except that GBS serum caused minor excess weight loss. Murine monoclonal antibody to Campylobacter jejuni and gangliosides also did not exacerbate disease. This experiment failed to show antibody-mediated disease exacerbation and so does not support an antibody-mediated mechanism in GBS.
Animals↗
Fine specificity of anti-GQ1b antibodies and clinical features.
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Antibody Specificity↗
The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies.
The clinical and laboratory phenotype of a paraproteinaemic neuropathy syndrome termed chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies is described in a series of 18 cases. Previous single case reports have outlined some features of this syndrome. All 18 cases were defined by the presence of serum IgM antibodies which react principally with NeuAc (alpha2-8)NeuAc(alpha2-3)Gal-configured disialosyl epitopes common to many gangliosides including GDlb, GD3, GTlb and GQlb. In 17 out of 18 cases, the serum contained benign IgM paraproteins, and in four of these cases at least two IgM paraproteins were present. The IgM antibodies were also cold agglutinins in 50% of cases. The clinical picture comprised a chronic neuropathy with marked sensory ataxia and areflexia, and with relatively preserved motor function in the limbs. In addition, 16 out of 18 cases had motor weakness affecting oculomotor and bulbar muscles as fixed or as relapsing-remitting features. When present in their entirety, these clinical features have been described previously under the acronym CANOMAD: chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies. This distribution of clinical features is reminiscent of Miller Fisher syndrome, in which acute-phase anti-disialylated ganglioside IgG antibodies are found. Clinical electrophysiology and nerve biopsy show both demyelinating and axonal features. A partial response to intravenous immunoglobulin and other treatments is reported in some cases.
Adult↗
Anti-GQ1b ganglioside antibodies mediate complement-dependent destruction of the motor nerve terminal.
Miller-Fisher syndrome is an autoimmune neuropathy characterized by ataxia, areflexia and ophthalmoplegia, and in the majority of cases the presence of high titres of anti-GQ1b ganglioside antibodies. In an ex vivo model, human and mouse anti-GQ1b antibodies have been shown previously to induce a complement-dependent alpha-latrotoxin-like effect on the murine motor endplate, i.e. they bring about massive quantal release of acetylcholine and eventually block neuromuscular transmission. Using immunofluorescence microscopy with image analysis, we show here that the late stages of this electrophysiological effect temporally coincide with the loss of heavy neurofilament (200 kDa) and type III beta-tubulin immunostaining and structural breakdown of the nerve terminal, as demonstrated by electron microscopy. Ultrastructurally, axon terminals were disorganized, depleted of vesicles, and subdivided by the infiltrating processes of capping Schwann cells. These findings provide clear pathological evidence to support a role for anti-ganglioside antibodies in mediating nerve terminal injury and further advance the view that this site may be of importance as a target in some human neuropathies.
Alkaline Phosphatase↗
Anti-GQ1b antibodies and evoked acetylcholine release at mouse motor endplates.
Miller Fisher syndrome (MFS) is clinically characterized by ataxia, areflexia, and ophthalmoplegia, and is associated with serum anti-GQ1b-ganglioside antibodies. We have previously shown that anti-GQ1b antibodies induce complement-dependent, alpha-latrotoxin-like effects at mouse neuromuscular junctions (NMJs) in vitro. This effect comprises a massive increase in spontaneous quantal acetylcholine (ACh) release, accompanied by block of evoked release and muscle paralysis. This mechanism may contribute to the motor features of MFS. Whether the block of evoked ACh release is a primary effect of anti-GQ1b antibodies or occurs secondary to massive complement-dependent spontaneous release is unknown. Using conventional micro-electrode methods, we measured in detail ACh release evoked with low- and high-rate nerve stimulation, and studied the effect on it of a purified MFS IgG and a mouse monoclonal anti-GQ1b IgM (without added complement). We found that evoked transmitter release was unaffected. Control experiments proved binding of anti-GQ1b antibody at the NMJ. We conclude that the block of nerve-evoked ACh release at the NMJ is not a primary effect of anti-GQ1b antibodies, but is dependent on antibody-mediated complement activation. It remains to be determined whether the block of nerve-evoked ACh release is the consequence of massive spontaneous ACh release or occurs as a concomitant event.
Acetylcholine↗
The application of control limits analysis to the myometric assessment of motor performance in neuropathy patients.
Measurement of muscle strength by myometry is used to monitor the natural course and treatment response of motor system diseases, both in individual patients and clinical trials. However, the practical usefulness of myometric data is reliant upon a statistical method for analysing serial strength measurements which distinguishes disease-related changes from random fluctuations in patient performance and operator/device dependent measurement errors. In this study we have applied control limits analysis to this problem. Using hand-held dynamometry, sets of baseline strength measurements were collected on two separate occasions during a period of clinical stability from up to four muscle groups in 22 patients with peripheral neuropathies. From these sets of data, 76 control limits were calculated and then used to describe the inter-measurement variation in muscle strength in individual muscles. The range of control limits was wide, varying from <10% of baseline (in 36% of muscles tested) to >50% (in 4% of muscles tested), with 88% of muscles falling within 30% of baseline. Follow-up data were also collected from all patients, including those undergoing treatment. Control limits analysis is a powerful and simple method for assessing the significance of motor performance changes in individual muscles in patients undergoing serial monitoring and can be easily applied to both single patients and clinical trials.
Adolescent↗
Randomized controlled trial of brain-derived neurotrophic factor in Guillain-Barré syndrome: a pilot study.
Brain-derived neurotrophic factor (BDNF) has the theoretical potential to protect neurones from axonal degeneration. The objective of this study was to discover whether brain-derived neurotrophic factor is safe in Guillain-Barré syndrome, and to make preliminary observations of its efficacy. This was a parallel group randomized controlled trial of subcutaneous brain-derived neurotrophic factor 25 microg/kg daily compared with placebo for up to 24 weeks or until patients could walk without aid. Six patients received brain-derived neurotrophic factor, of whom three had serious adverse events including one death. Four patients received placebo, of whom two had serious adverse events including one death. The rate and extent of recovery were similar in the two groups. This pilot study did not detect any serious adverse events attributed to brain-derived neurotrophic factor treatment.
Adolescent↗
EFNS task force report: a questionnaire-based survey on the service provision and quality assurance for determination of diagnostic autoantibody tests in European neuroimmunology centres. European Federation of Neurological Societies.
Autoantibodies to a wide variety of neural components are frequently sought in the sera of patients with neurological diseases suspected to have an antibody-associated autoimmune basis. Variations in assay methodology and availability are likely to exist throughout European diagnostic immunology centres, and interlaboratory discrepancies in performance for some assays have been reported. The availability of quality assurance is largely unknown. In this questionnaire-based EFNS task force, all 18 national representatives of the Neuroimmunology Panel within the EFNS were invited to estimate the service provision within their country; 12 panel members responded. From these responses, it emerged that a range of assays are being performed throughout European centres, involving over 20 separate antigens, using a broad array of immunodetection techniques. With the exception of the estimation of anti-AChR antibodies for the diagnosis of myasthenia gravis, no systematic quality assurance schemes are available, this being conducted on an ad hoc basis, or not at all. Since quality is a central component of assay sensitivity and specificity, we conclude that there is an urgent need to introduce pan-European quality assurance schemes, based on provision of positive and negative test sera from a central source, and in which all neuroimmunology laboratories should participate.
Autoantibodies↗
The role of antiglycolipid antibodies in peripheral neuropathies.
The role of antiglycolipid antibodies in peripheral neuropathy continues to be defined in terms of clinical-serological associations and innovative experimental work establishing the role of these antibodies in pathogenesis. The present review focuses on the major developments in this field over the past 12 months.
Antibodies↗
Peripheral neuropathy associated with anti-GM2 ganglioside antibodies: clinical and immunopathological studies.
GM2 ganglioside is a potential peripheral nerve antigen for neuropathy-associated autoantibodies. However little data are available on their pathogenic effects, if any. In this study we have screened both neuropathy-associated and control sera for anti-GM2 antibodies and subsequently used high titre sera for immunohistological and complement mediated cytotoxicity studies. We identified abnormally elevated anti-GM2 antisera in the normal population, as well as in patients with peripheral neuropathies and other neurological diseases. GM2 antibodies were either mono-reactive, cross-reactive with GM1a, or cross-reactive with GalNAc-GM1b and/or GalNAc-GD1a. All GM2 antisera from neuropathy subjects and normal controls bound to, and were capable of complement-mediated lysis of the NSC-34 cell line which expresses high levels of membrane-associated GM2. However, in immunohistological studies on human and rodent peripheral nervous system tissues, no specific binding was seen with GM2 antisera, either cross-reactive with GalNAc-GM1b and GalNAc-GDla, or with GM1a. These data indicate that although GM2 antisera can lyse neural membranes containing GM2, this antigen(s) is not detectable by standard immunohistological techniques in human or rodent peripheral nerve. This raises doubts about their pathophysiological significance in human autoimmune neuropathy.
Adolescent↗